WO2014188729A1 - Composition pour administration orale - Google Patents

Composition pour administration orale Download PDF

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Publication number
WO2014188729A1
WO2014188729A1 PCT/JP2014/002710 JP2014002710W WO2014188729A1 WO 2014188729 A1 WO2014188729 A1 WO 2014188729A1 JP 2014002710 W JP2014002710 W JP 2014002710W WO 2014188729 A1 WO2014188729 A1 WO 2014188729A1
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Prior art keywords
oral composition
composition
total amount
group
mass
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PCT/JP2014/002710
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English (en)
Japanese (ja)
Inventor
啓達 藤井
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持田製薬株式会社
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Priority to JP2014540253A priority Critical patent/JPWO2014188729A1/ja
Publication of WO2014188729A1 publication Critical patent/WO2014188729A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to an oral composition having an improved unpleasant odor caused by diacetyl emitted by a specific pharmaceutical product.
  • olmesartan medoxomil is an antihypertensive drug already manufactured and sold as Olmetec (registered trademark, hereinafter the same) tablet.
  • Olmetec tablets are uncoated tablets containing olmesartan medoxomil as an active ingredient.
  • Olmesartan medoxomil is known to release low-molecular 2,3-butadione (hereinafter referred to as “diacetyl”), which is considered to be an odor-causing substance, in the process of gradual cleavage of medoxomil ester (patent) Reference 1).
  • Olmetec tablets are Medet (registered trademark, hereinafter the same) tablets whose active ingredients are metformin hydrochloride and Metogluco (registered trademark, the following) tablets, and Foypan (registered trademarks, the following) whose active ingredients are camostat mesylate. It is also known that these tablets are colored when they are encapsulated with a tablet, and this is considered to be caused by diacetyl released from Olmetec tablets. The coloration of the tablet by encapsulating not only impairs the appearance but also may affect the quality of the drug itself, which is not preferable. For these reasons, there has been a need for a device that does not generate or release diacetyl from a pharmaceutical preparation containing olmesartan medoxomil.
  • a method for preventing the generation of odor a method of adding a substance that suppresses the generation of odor to the uncoated tablet or a substance that adsorbs the generated diacetyl can be considered.
  • a method of adding cyclodextrin to a pharmaceutical composition formulation containing a compound having a medoxomil group as an active ingredient is known (see Patent Document 1).
  • Patent Document 1 a method of adding cyclodextrin to a pharmaceutical composition formulation containing a compound having a medoxomil group as an active ingredient.
  • cyclodextrin used in this method has a function of inclusion of low molecules in structure, but there is a risk of inclusion of various low molecules, not limited to diacetyl. May reduce the effectiveness of the drug.
  • Patent Document 2 As a method for stabilizing olmesartan medoxomil, an increase in impurities can be suppressed by adding stearic acid in an amount of 0.1 to 1% by mass based on the total amount of the uncoated tablet or 1 to 20% by mass based on the active ingredient (Patent Document 2). See).
  • Patent Document 3 describes a specific example in which about 1% by mass of stearic acid is blended with respect to the total amount of uncoated tablets. Even if stearic acid is blended in this amount, a problem arises in fluidity. It is described as inappropriate.
  • the use of stearic acid to solve odors is not described.
  • the present inventors have intensively studied for the purpose of generating and / or suppressing the release of diacetyl from oral preparations. It was found that the odor can be suppressed by adding an acid. In addition, when high content of stearic acid is added to the uncoated tablet, there is a problem that the fluidity decreases as described above. It was found that tablets can be produced with good manufacturability when used in the above.
  • the first aspect of the present invention is the following oral composition.
  • (1-1) a) a drug having a medoxomil group as an active ingredient, and b) 5 to 15% by weight of saturated fatty acids having 12 to 22 carbon atoms based on the total amount of the composition,
  • An oral composition comprising (1-2) The oral composition according to (1-1), wherein the drug having a medoxomil group is olmesartan medoxomil.
  • the oral composition further comprises c) crospovidone, pregelatinized starch, or a mixture thereof as a disintegrant, according to any one of (1-1) to (1-3) Oral composition.
  • (1-5) The oral composition according to (1-4), wherein crospovidone, pregelatinized starch, or a mixture thereof as a disintegrant is 2 to 20% by mass based on the total amount of the composition.
  • the oral composition further comprises d) at least one selected from the group consisting of anhydrous lactose, lactose hydrate, sucrose, trehalose, and mannitol as an excipient (1-1) to (1-1)
  • the oral composition further includes at least one selected from the group consisting of d) anhydrous lactose, lactose hydrate, and sucrose as an excipient (1-1) to (1-6) Orally.
  • d) further comprises anhydrous lactose and / or sucrose as an excipient.
  • blending amount of the excipient is 65 to 90% by mass, preferably 70 to 90% by mass, based on the total amount of the composition Orally.
  • An oral composition comprising (1-12) The oral composition according to (1-11), wherein the excipient is anhydrous lactose and / or sucrose.
  • (1-19) a) Olmesartan medoxomil, b) a saturated fatty acid selected from 5 to 15% by weight of stearic acid or palmitic acid based on the total amount of the composition; c) at least one disintegrant selected from the group consisting of crospovidone, pregelatinized starch, and mixtures thereof; d) at least one excipient selected from the group consisting of anhydrous lactose, lactose hydrate, and sucrose;
  • the second aspect of the present invention is the following method for producing an oral composition.
  • (2-1) a) a drug having a medoxomil group as an active ingredient, b) 5 to 15% by weight of saturated fatty acids having 12 to 22 carbon atoms based on the total amount of the composition, c) at least one disintegrant selected from the group consisting of crospovidone, pregelatinized starch, and mixtures thereof in an amount of 2 to 20% by weight based on the total amount of the composition; d) Oral in the form of a tablet containing 65-90% by mass of the total amount of the composition, at least one excipient selected from the group consisting of anhydrous lactose, lactose hydrate, sucrose, trehalose, and mannitol.
  • a method for producing a composition for use comprising: The manufacturing method characterized by including the process of mixing said a) thru
  • a manufacturing method comprising: The manufacturing method characterized by including the process of mixing said a) thru
  • (2-5) The production method according to (2-4), comprising the steps of mixing a) to d) and dry granulating the mixture.
  • (2-6) The production method according to (2-4) or (2-5), further comprising a tableting step after the mixing step a) to d).
  • (2-7) including the steps of mixing a) to d), tableting the mixture to form a slug tablet, sizing the tablet, and tableting the granulated powder (2-1) ) To (2-6).
  • (2-8) a) Olmesartan medoxomil, b) 5 to 15% by weight of stearic acid, based on the total amount of the composition, c) at least one disintegrant selected from the group consisting of crospovidone, pregelatinized starch, and mixtures thereof in an amount of 2 to 20% by weight based on the total amount of the composition; d) An oral composition in the form of a tablet containing 65 to 90% by mass of at least one excipient selected from the group consisting of anhydrous lactose, lactose hydrate, and sucrose, based on the total amount of the composition
  • a manufacturing method comprising: A step of mixing a) to d), a step of tableting the mixture into a slug tablet, a step of sizing the tablet, and a step of tableting the powder after sizing (2-1) to The production method according to (2-7).
  • the said manufacturing method when mixing said a) thru
  • the oral composition of the present invention the generation and / or release of diacetyl is significantly suppressed as compared with the case where no saturated fatty acid is contained, and no odor or odor is significantly suppressed. Therefore, the oral composition of the present invention can be made into tablets and granules having good dosing properties without coating for suppressing odor release.
  • the oral composition of the present invention is excellent in fluidity by blending a large amount of a specific additive having high fluidity, even though it contains a large amount of saturated fatty acid such as stearic acid. It is excellent in manufacturability and can be manufactured industrially.
  • the oral composition of the present invention has good drug elution.
  • the oral composition of the present invention preferably has any two effects. More preferably, it has all the effects.
  • the present invention is described in detail below.
  • it is essential to add a saturated fatty acid in order to suppress the generation and / or release of diacetyl.
  • the saturated fatty acid in the present invention include linear saturated fatty acids having a total carbon number of 12 to 22, preferably 15 to 20, and more preferably 16 to 18. Specific examples include stearic acid, palmitic acid, myristic acid, arachidic acid, behenic acid, lauric acid, stearic acid or palmitic acid is particularly preferable, and stearic acid is more preferable.
  • These saturated fatty acids can be used in combination of two or more.
  • the saturated fatty acid is preferably contained in an amount of 5 to 15% by mass, more preferably 5 to 10% by mass, and further preferably 7 to 9% by mass, based on the total mass of the oral composition of the present invention.
  • stearic acid commercially available ones can be used.
  • stearic acid Shin Nippon Rika, Nippon Seika
  • Purified stearic acid Kao
  • stearic acid series lion
  • JP stearic acid Oil industry
  • the oral composition of the present invention may further contain a disintegrant.
  • the disintegrant is not particularly limited as long as it has a small effect on the degradation of olmesartan medoxomil. Whether or not the disintegrant to be used affects the decomposition of the drug can be examined with reference to a test example (for example, see Test Example 5) described later.
  • Preferred disintegrants in the oral composition of the present invention include, for example, polyvinylpyrrolidone, crospovidone, pregelatinized starch, carmellose and salts thereof, croscarmellose sodium, corn starch, potato starch, hydroxypropyl starch and the like. .
  • Examples of the salt of carmellose include carmellose calcium and carmellose sodium.
  • polyvinyl pyrrolidone examples include Aifact K-30 (Daiichi Kogyo Seiyaku), Kollidon (BASF Japan), Plusdon (IS Japan, Gokyo Sangyo) and the like.
  • crospovidone examples include crospovidone (DSP Gokyo Food & Chemical), Kollidon (BASF Japan), and polyplastidone (ISP Japan).
  • alpha starch examples include SWELSTAR (Asahi Kasei Chemicals), LYCATAB PGS (Rocket Japan), Amicol (Nissho Chemical), and the like.
  • Alphalated starch also includes partially pregelatinized starch.
  • partially pregelatinized starch examples include LYCATAB C (Rocket Japan), PCS (Asahi Kasei Chemicals), Starch 1500 (Nippon Colorcon), and Fiboze (Nissho Chemical).
  • the mass ratio of saturated fatty acid to disintegrant is preferably 1: 0.2 to 1: 4, more preferably 1: 0.5 to 1: 1.5.
  • the excipient contained in the uncoated tablet together with the saturated fatty acid is not particularly limited as long as it has a small effect on the degradation of olmesartan medoxomil.
  • anhydrous lactose, lactose hydrate, sucrose, trehalose, mannitol, sorbitol examples include tall and xylitol, and anhydrous lactose and sucrose are preferred.
  • Anhydrous lactose is more preferred.
  • Examples of anhydrous lactose include SuperTab (DFE Pharma) and Lactopress Anhydrous (DFE Pharma).
  • sucrose include sucrose (Mitsui Sugar, Taikaku, Nissin Sugar).
  • the excipient used in the oral composition of the present invention is not particularly limited as long as it has improved fluidity and good manufacturability even if it contains a saturated fatty acid such as stearic acid.
  • a preferred range for the dosage form is 65% by mass or more of the whole oral composition, more preferably 70% by mass or more, and further preferably 75% by mass or more. Further, it is preferably 65 to 90% by mass, more preferably 70 to 90% by mass, still more preferably 70 to 85% by mass, and particularly preferably 75 to 85% by mass.
  • the mass ratio of stearic acid to excipient is preferably 1: 3 to 1:20, more preferably 1: 5 to 1:15.
  • the form of the oral composition in the present invention is not particularly limited, and examples thereof include tablets, capsules, powders, fine granules, granules, troches and the like, and tablet forms are particularly preferable.
  • the oral composition of the present invention can be used as a pharmaceutical preparation as it is, but a coating layer can be further formed. Since the oral composition of the present invention can suppress unpleasant odor caused by the drug itself, a coating layer for suppressing the unpleasant odor is not particularly necessary, but a coating layer as necessary as a preparation. Can also be provided.
  • the component and film thickness of the coating layer are not particularly limited, but it is preferably a film thickness that can more effectively suppress the unpleasant odor of the drug, for example, 1 ⁇ m to 300 ⁇ m, preferably 1 ⁇ m to 200 ⁇ m. Particularly preferably, the thickness is 1 to 50 ⁇ m.
  • the oral composition of the present invention can use a wide variety of known pharmaceutical carriers in the pharmaceutical technology field as necessary.
  • lactose other than those mentioned above, sucrose, mannitol, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, silicate and other excipients, water, ethanol, simple syrup, glucose solution, starch solution, Binders such as gelatin solution, carboxymethylcellulose, carboxymethylcellulose Na, shellac, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, gelatin, dextrin, pullulan; citric acid, anhydrous citric acid, sodium citrate, sodium citrate PH adjusters such as hydrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, sodium hydrogen phosphate, anhydrous disodium hydrogen phosphate; carmellose calcium, low substituted hydroxy Disintegrating agents such as lopicellulose, carmellose,
  • the oral composition of the present invention is selected from the group consisting of at least one disintegrant selected from the group consisting of crospovidone, pregelatinized starch, or a mixture thereof, and anhydrous lactose, lactose hydrate, and sucrose.
  • the combination of disintegrant and excipient is not particularly limited, but crospovidone and anhydrous lactose, crospovidone and lactose hydrate, crospovidone and sucrose, pregelatinized starch and Anhydrous lactose, pregelatinized starch and lactose hydrate, pregelatinized starch and white sugar, mixture of crospovidone and pregelatinized starch and anhydrous lactose, mixture of crospovidone and pregelatinized starch and lactose hydrate, crospovidone and pregelatinized starch And a combination of sucrose.
  • crospovidone and anhydrous lactose particularly preferred is a combination of crospovidone and anhydrous lactose, crospovidone and lactose hydrate, crospovidone and sucrose, and the most preferred combination is crospovidone and anhydrous lactose.
  • the drug used in the oral composition in the present invention is not particularly limited as long as it produces an unpleasant odor, but for the purpose of the present invention, a medoxomil group ((5-methyl-2-oxo-1,3-dioxole) is used. Those having -4-yl) methyl) are suitable, and those that generate diacetyl are particularly preferred. What emits an unpleasant odor includes not only the fact that an odor is actually generated, but also a case where there is a possibility of generating the odor. Examples thereof include olmesartan medoxomil, which is a hypertensive drug, purifloxacin, which is an antibacterial drug, and lenampicillin hydrochloride.
  • the compounding quantity of the said medicine in the composition for oral use of this invention It is 1 mass% or more with respect to the composition whole quantity, More preferably, it is 2 mass% or more, More preferably, it is 3 mass% or more. is there. Further, it is preferably 1 to 25% by mass, more preferably 2 to 20% by mass, particularly preferably 3 to 15% by mass, and particularly preferably 7 to 12% by mass.
  • other drugs can be used in combination as necessary.
  • a compounding agent containing a drug such as olmesartan medoxomil may be used.
  • the oral composition of the present invention is characterized in that even if it is encapsulated, it does not easily change its formulation with other drugs and suppresses quality deterioration such as coloring.
  • Such other drug is not particularly limited as long as it causes a change in formulation due to diacetyl, and examples thereof include a drug having a guanidino group.
  • Examples of drugs having a guanidino group include metformin, camostat mesylate, zanamivir hydrate, cetrorelix acetate, tegaserod maleate, desmopressin acetate, eptifibatide, bivalirudine, ganirelix acetate, buserelin acetate, famotidine, triptorelin pamoate, pinacidil, Examples include histrelin, thymopentatin, adrenochrome guanylhydrazone mesylate, cimetidine, benexate hydrochloride betadex, gusperimus hydrochloride, nafamostat mesylate, guanabenz acetate, argatroban, and pharmaceutically acceptable salts thereof.
  • Metformin hydrochloride is a therapeutic agent for diabetes
  • camostat mesilate is a therapeutic agent for reflux esophagitis.
  • the method for producing the oral composition of the present invention as a tablet is not particularly limited, but a direct compression method or tableting after dry granulation is preferred.
  • the presence or absence of an unpleasant odor can be determined by “characteristic: confirmation of odor” in Test Example 1 described later.
  • Characteristic: confirmation of odor for 10 mg of a drug having a medoxomil group, the odor of a tablet immediately after production or sealed in a glass vial with a volume of 20 mL and stored for a predetermined temperature and period is 0.5 units according to the evaluation criteria described later. Evaluate with.
  • the odor is expressed by a score, but is preferably 1.5 or less, more preferably 1.0 or less, and further preferably 0.5 or less. The specific definition of the score will be described later.
  • the quantification of diacetyl can be performed by gas chromatography of Test Example 2 described later. This method can quantitatively evaluate the amount of diacetyl that causes odor.
  • the value of diacetyl is expressed as a value relative to the amount of the drug having a medoxomil group, and 40 days at 40 ° C. per 1 mg of the drug having a medoxomil group.
  • it is preferably 200 ng / mg or less, more preferably 100 ng / mg or less, and further preferably 70 ng / mg or less.
  • the unique unpleasant odor of drugs having a medoxomil group such as olmesartan medoxomil is due to diacetyl. Therefore, even when the odor score was evaluated by a human, a certain correlation was observed between the odor score and the diacetyl value. If the odor rating is 1.5 or less, diacetyl is about 200 ng / mg or less, 1.0 is about 100 ng / mg or less, and 0.5 is about 70 ng / mg or less. Conceivable.
  • the oral composition in the present invention preferably has good dissolution properties.
  • test solution Japanese Pharmacopoeia dissolution test solution, 2 rotations: 50 rotations
  • the elution rate is 50% or more, preferably 60% or more, more preferably 80% or more.
  • Example 1 After mixing olmesartan medoxomil 20.0 g, anhydrous lactose 167.0 g, stearic acid 17.0 g, crospovidone 10.0 g, and sodium stearyl fumarate 2.0 g, the diameter is 7.0 mm and the mass per tablet is 108 mg. Tableting was performed to obtain an uncoated tablet.
  • Example 2 After mixing olmesartan medoxomil 20.0 g, anhydrous lactose 167.0 g, stearic acid 17.0 g, pregelatinized starch 10.0 g, and sodium stearyl fumarate 2.0 g, the diameter is 7.0 mm and the mass per tablet is 108 mg. To obtain a plain tablet.
  • Example 3 After mixing olmesartan medoxomil 20.0 g, anhydrous lactose 162.0 g, stearic acid 17.0 g, pregelatinized starch 15.0 g, and sodium stearyl fumarate 2.0 g so that the diameter becomes 7.0 mm and the mass per tablet 108 mg To obtain a plain tablet.
  • Example 4 After mixing olmesartan medoxomil 20.0g, anhydrous lactose 177.0g, stearic acid 17.0g, and sodium stearyl fumarate 2.0g, it was compressed to 7.0mm in diameter and 108mg in weight per tablet. Got.
  • Example 5 After mixing 20.0 g of olmesartan medoxomil, 177.0 g of sucrose, 17.0 g of stearic acid, and 2.0 g of sodium stearyl fumarate, the tablet was compressed to a diameter of 7.0 mm and a mass of 108 mg per tablet. Obtained.
  • Table 1 shows the formulations of Examples 1 to 5 and Comparative Example 1 (each component content when the active ingredient content is 10 mg).
  • Example 6 For the same composition as in Example 3, tablets were produced using dry granulation. After mixing olmesartan medoxomil 20.0g, anhydrous lactose 81.0g, stearic acid 17.0g, pregelatinized starch 15.0g, sodium stearyl fumarate 1.0g, diameter 12.0mm, mass per tablet about 0.3g Tableting was performed to obtain a slug tablet. Slug tablets were sized using a sizing machine, 69.52 g of anhydrous lactose and 0.86 g of sodium stearyl fumarate were added to and mixed with 115.0 g of the sized powder, and the mass per tablet was 7.0 mm in diameter. Tableting was performed to obtain 108 mg to obtain an uncoated tablet.
  • Test Example 1 The characteristics of the tablets were evaluated by the following methods.
  • Test Example 1 ⁇ Properties: Confirmation of Odor> The odor immediately after production or one tablet in a 20 mL glass vial was sealed and sealed, and the odor after storage under predetermined conditions was evaluated.
  • the odor scores are as follows, and the scores are given in 0.5 increments.
  • Table 2 shows the test results.
  • Table 2 summarizes the results of Comparative Example 1 when the preparations of Examples 1 to 6 and Comparative Example 1 were stored immediately after production or stored at 25 ° C. for 4 weeks. The preparation is sealed and stored in a 20 mL capacity glass vial. In such a case, there is no influence of the humidity of the outside air. The same applies to the following.
  • Test Example 2 ⁇ Quantitative determination of diacetyl by gas chromatography>
  • One tablet containing 10 mg of olmesartan medoxomil was placed in a 20 mL capacity gas chromatography vial and sealed. After storing this vial under predetermined conditions, headspace gas was injected into gas chromatography, and the concentration of diacetyl was measured.
  • Table 3 summarizes the results of Test Example 2 when the preparations of Examples 1, 3, 4 and Comparative Example 1 were stored at 25 ° C. for 4 weeks and at 40 ° C. for 5 days, respectively.
  • the test results show the amount of diacetyl (ng / mg) generated from 1 mg of olmesartan medoxomil.
  • the measurement conditions for gas chromatography are shown below.
  • Examples 1 to 5 containing stearic acid have an odor rating of 0.5 to 1.5 immediately after production, whereas the formulation of Comparative Example 1 is 2.5, which is saturated. It was confirmed that the oral composition of the present invention containing a fatty acid clearly suppressed odor.
  • Table 3 shows the evaluation result of diacetyl as a causative substance of odor. When stored at 25 ° C. for 4 weeks, it can be confirmed that in Examples 1 and 3 containing stearic acid, the amount of diacetyl is sufficiently suppressed as compared with Comparative Example 1, and the smell is small. Further, even in an accelerated test at 40 ° C. for 5 days, the difference between Example 4 containing stearic acid and Comparative Example 1 not containing it is clear.
  • Example 3 is a direct compression method, and Example 6 has the same formulation as Example 3. However, after dry granulation, the tablet is compressed and manufactured. Table 2 shows the odor scores immediately after production and at 25 ° C. for 4 weeks. The results are almost the same, and it can be confirmed that any method can be used.
  • Test Example 3 Evaluation of Related Substances>
  • the sample solution and the standard solution were analyzed by high performance liquid chromatography, and the amount of related substances (%) in the tablets was measured.
  • the related substances refer to impurities contained in olmesartan medoxomil drug substance and the like, and degradation products of olmesartan medoxomil.
  • the amount of the related substance is calculated from olmesartan medoxomil contained in the standard solution and represents the amount of the related substance contained in the sample solution expressed in%.
  • the maximum value represents the amount of the related substance of the largest peak when evaluated by high performance liquid chromatography, and the total value represents the amount of the related substance when the peaks of the related substances are totaled.
  • Example solution> After precisely weighing the weight of one tablet, this tablet was ground in a mortar and accurately weighed into a volumetric flask. Acetonitrile was added to this and irradiated with ultrasonic waves, and then acetonitrile was added to make exactly 20 mL. 4 mL of this solution was accurately taken, 1 mL of acetonitrile was added, and then mobile phase A was added to make exactly 10 mL to obtain a sample solution. ⁇ Standard solution> Separately, 20.0 mg of olmesartan medoxomil was accurately weighed and acetonitrile was added to make exactly 50 mL.
  • Table 5 summarizes the results of Test Example 3 when the preparations of Examples 1 to 5 and Comparative Example 1 were stored immediately after production and at 40 ° C. for 5 days, respectively.
  • Table 5 shows the amount (%) of related substances generated in the tablets immediately after production and after storage at 40 ° C. for 5 days.
  • the amount of related substance (%) after storage at 40 ° C. for 5 days is increased in Comparative Example 1 as compared with Example 4, and the addition of stearic acid suppresses the increase in related substances. I can confirm.
  • Examples 1 to 5 and Comparative Example 1 showed the similar results for the similar substances in both the maximum value and the total value.
  • Comparative Example 1 had a higher odor rating than Examples 1-5, while there was no difference in related substances.
  • Diacetyl the cause of odor, is thought to be generated by the degradation of olmesartan medoxomil, but even if there is no difference in the related substances, the difference in odor rating is significant, so the odor is not necessarily the value of the related substances. It can be seen that there is no correlation.
  • Test Example 4 ⁇ Elution test> Examples 1 and 4, Comparative Example 1 and one commercially available Olmetec tablet 10 mg tablet were subjected to a dissolution test under the following conditions by the paddle method of the Japanese Pharmacopoeia dissolution test. Table 6 shows the dissolution rate (%) of olmesartan medoxomil from each tablet. ⁇ Test conditions> Test solution: Japanese Pharmacopoeia dissolution test 2 solution Rotation speed: 50rpm Test solution temperature: 37 ° C Test solution volume: 900 mL
  • the Olmetec tablets in Table 6 are tablets containing low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, crystalline cellulose, lactose hydrate, and magnesium stearate as additives.
  • Example 4 is a formulation containing stearic acid, it can be confirmed that the dissolution properties are significantly reduced as compared with Comparative Example 1 which does not contain stearic acid.
  • Example 1 using a disintegrating agent the dissolution property was remarkably improved as compared with the formulation of Example 4 not containing a disintegrating agent.
  • the tablets had excellent dissolution properties.
  • Test Example 5 Olmesartan medoxomil and each disintegrant listed in Table 7 below (Property: Confirmation of odor (60 ° C, 1 week sealed environment)) and Table 8 (Related substances (60 ° C, 1 week sealed environment)) were mixed at a ratio of 1: 1. Then, the odor (Table 7) and the evaluation of related substances (Table 8) when stored in a sealed environment at 60 ° C. for 1 week were performed. The method follows the method described above.
  • olmesartan medoxomil In formulations containing olmesartan medoxomil and stearic acid, dissolution is reduced, so it is preferable to add a disintegrant, but hypromellose, hydroxypropylcellulose, and crystalline cellulose contain these in order to increase the related substances of olmesartan medoxomil. It is not preferable to make it.
  • crospovidone and pregelatinized starch are considered to be suitable as disintegrants in the oral composition of the present invention because the increase in related substances is small and the generation of odor is small compared to other disintegrants.

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Abstract

L'invention fournit une composition pour administration orale présentant une amélioration en termes de mauvaise odeur caractéristique provoquée par un diacétyle et dégagée par des produits pharmaceutiques spécifiques. Plus précisément, l'invention fournit une composition pour administration orale constituée par mélange d'un acide gras saturé dans cette composition pour administration orale contenant un principe actif produisant du diacétyle. La composition pour administration orale de l'invention empêche la mauvaise odeur, et possède des propriétés de fabrication simples et des propriétés de dissolution satisfaisantes.
PCT/JP2014/002710 2013-05-24 2014-05-23 Composition pour administration orale WO2014188729A1 (fr)

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JP2017001999A (ja) * 2015-06-12 2017-01-05 富士フイルム株式会社 薬物含有粒子の製造方法、薬物含有粒子、医薬組成物、及び口腔内崩壊錠

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